EM Nerd-The Case of the Otalgic Squire

As the year draws to a close it is safe to say that it has not been a productive twelve months for antibiotic stewardship in the Emergency Department. A recent example is the latest NEJM publication by Hoberman et al examining the efficacy of antibiotics for children with acute otitis media (OM) (1).

Using a non-inferiority trial design, the authors compared the use of the traditional 10-day course of antibiotics to an abbreviated 5-day course in children less than two years of age presenting with acute OM. 520 children ranging from 6-23 months were randomized to either a 10-day course of amoxicillin–clavulanate or a 5-day course followed by 5-days of placebo. The patients were followed up for 14 days to assess the effectiveness of their treatment. Caregivers were also asked to return to the office every 6-weeks for a follow-up visit until the end of the respiratory infection session (October-May).

The authors reported that the trial was stopped short of its 600 patient recruitment goal because of overwhelming success in the patients who received the 10-day course of antibiotics. 16% of patients in the 10-day group experienced clinical failure at or before the 14-day assessment, compared to 34% in the 5-day group. The authors noted the absolute benefit to prolonged antibiotic therapy was 18% or an NNT of 6 to prevent one-treatment failure.

This benefit remained consistent over the various subgroups examined including: age, the number of ears affected, severity, exposure to other children, and initial otoscopic evaluation.

And yet before we jovially hand out long courses of broad-spectrum antibiotics to all the good little children presenting to our Emergency Departments complaining of otalgia, it is imperative we examine these results in their proper context.

The majority of evidence examining the benefits of antibiotic therapy for the treatment of otitis media when compared to placebo has been overwhelmingly unimpressive. The 2015 Cochrane review by Venekamp et al examined 13 trials with over 3400 patients and found that the use of antibiotics only minimally reduced the overall symptom burden related to OM (2). By 24-hours, 60% of the patients experienced symptom resolution whether or not they received antibiotics. At 12-14 days there was a 14% reduction in the number of patients who had absolute symptom resolution in those who received antibiotic therapy. This small benefit came at the cost of a significant increase in the rate of diarrhea, vomiting and diaper rash (7% absolute increase).

And so how should we explain the fantastic results reported by Hoberman et al when comparing a 10-day course of antibiotics to a 5-day course?

How can a 5-day course of antibiotics be inherently worse than placebo?

As always the answer lies in how you choose to define success.

This recent paper is not the first publication these authors have produced examining the use of antibiotics in OM. In 2011 the very same author group published an RCT in the NEJM examining the use of a 10-day course of amoxicillin–clavulanate to placebo (3). Using almost identical inclusion criteria, the authors randomized 291 children presenting with acute OM to either amoxicillin–clavulanate or placebo. Unlike their most recent publication, this trial was far less impressively in favor of antibiotic use. In fact, if it was not for a degree of methodological hanky panky, the trial would have been considered negative (4). The authors reported an improvement in the number of children who experienced a sustained resolution of symptoms over the 10-day course of antibiotic therapy. And while this endpoint was indeed statistically significant (p=0.04), it was not their originally intended primary endpoint. In fact, their original primary endpoint as reported on clinicaltrials.gov was the frequency of initial symptom resolution, which failed to reach statistical significance. And while this trial may have been underpowered to detect the small benefit in relief of symptoms reported by the Cochrane analysis, it is certainly nowhere near as impressive as the results presented in their most recent paper.

Unlike their 2011 paper, in the most recent publication Hoberman at al selected a primary end point a priori and stuck to it. In this case it was “the percentage of children who had clinical failure after treatment of the index infection”. They defined this as the worsening of symptoms or otoscopic signs of infection (primarily tympanic membrane bulging), or if the patients did not have complete or nearly complete resolution of symptoms and signs attributable to acute otitis media by the end of treatment. When this vague composite endpoint was employed, the clinical failure rate was 16% and 34% in the 10-day and 5-day groups respectively. Applying the same definition to their 2011 article, the rate of clinical failure was 16% and 51% in the antibiotic and placebo groups respectively.

And so it appears that this composite outcome is what differentiates these results from the remainder of the literature. But does this definition of clinical failure translate into clinically meaningful outcomes for the patients? The Cochrane authors reported in their 2015 meta-analysis a clear improvement in otoscopic findings in patients who received antibiotics compared to those who received placebo. Do otoscopic findings on follow up really hold any clinical meaning? After all, do children from 6 to 23 months really care about the appearance of their tympanic membrane in the weeks following their ear infections?

In Hoberman et al’s original paper there was a 35% absolute difference in the number of patients who experienced clinical failure. Unfortunately, it is difficult to decipher the individual elements that make up this mysterious composite outcome. But what is clear is that the difference in pain and discomfort was minimal. 80% of the patients randomized to receive antibiotics reported symptom resolution at 7-days, compared to 74% in the placebo group. This 6% absolute difference was not statistically significant.

The most recent trial’s results are fairly similar. The authors reported an 18% difference in the rate of clinical failure at 10-12 days as their primary endpoint, but pain and discomfort reported between the patients in the 10 and 5 day groups using the Acute Otitis Media–Severity of Symptoms (AOM-SOS) scale, was only minimally different. In fact, all the mean pain scores reported by the authors, though statistically different, were all far below what is considered the minimally important difference (MID) (5). The only signal of benefit observed was that patients randomized to the 10-day course of antibiotics more frequently reported a greater than 50% reduction in pain (91% vs 80%, p= 0.03). This 10% difference in pain scores is fairly similar to the previous modest benefits attributed to antibiotic therapy for acute OM.

The authors should be commended on the methodological rigor of their most recent escapades into antimicrobial therapy of acute OM. Unfortunately, I fear the results of this trial are presented in such a perplexing manner they will inevitably be used to justify the widespread use of antibiotic therapy for the treatment of acute OM. More importantly these results subtly shift the question from, “Do patients presenting with acute OM require antibiotic therapy?” to “How long should patients with acute OM receive antibiotic therapy?”

Although antibiotic therapy has consistently demonstrated meager benefits in the form of symptom relief, it is not without its harms. In their original 2011 paper, Hoberman et al reported a 10% increase in the rate of diarrhea and a 16% increase in the portion of children with diaper rashes (a harm that is hidden in their most recent paper as a 5-day course of amoxicillin–clavulanate is just as diarrhea inducing as 10-days). Especially since a wait and watch strategy has been shown to provide a similar degree of symptom relief (2) with far fewer side effects experienced.

It’s also interesting to note that the AAP recommends high dose amoxicillin (80-90mk/kg in two divided doses per day) as first line treatment with co-amoxiclav suggested for those who have had amoxicillin in the previous 30 days, have concurrent conjunctivitis, or there is a high likelihood of beta-lactamase producing organisms. (1)
The fact that the lead author holds a patent for a formulation of co-amoxiclav strikes me as a major COI.

Both the AAP and CPS recommend high-dose amoxicillin alone as the first line therapy (if you’re going to give abx, which we often do not need to… the wait-and-see-approach is fine!). Interesting that amox/clav is used in this study given the conflict of interest of the primary author holding a patent on amox/clav…